Administration of lymphocytes or tumor cells transduced with specific cytokine genes represent novel approaches for the treatment of cancer. By either providing antitumor effector cells or stimulating antitumor immunity at the tumor site these experimental modalities have resulted in decreased tumorigenicity and regression of existing tumors in a number of experimental models. Recently, retroviral-mediated transfer in vivo of a herpes-virus-derived thymidine kinase (tk) gene into a proportion of brain glioma tumor cells rendered them sensitive to destruction by an antiviral drug. It also led to death of other tumor cells, not transduced with the tk gene, through a poorly defined bystander effect. In spite of these experimental results, the targeting of effector lymphocytes as well as anticancer cytokines and drug sensitivity factors to particular tumor sites has had limited clinical applications because it involves relatively complex procedures not widely available. We considered the possibility that tumor cell killing might be induced by inoculation of the tumor-bearing host with benign cells which are normally destroyed if inoculated into the same host. We reasoned that by stimulating a local cytotoxic response in vivo one might achieve killing of tumor cells through a bystander effect. When injected subcutaneously into irradiated athymic (nude) mice, human B cells immortalized with Epstein-Barr virus (EBV) either fail to grow or give rise to small tumors that soon regress through necrosis and scarring. The mechanism for this regression is not fully understood but has been attributed to residual host immunity. In the same experimental system, human Burkitt's lymphoma cells generally develop into lethal malignant tumors. In the present study, we examined whether inoculation of EBV- immortalized B cells might have an antitumor effect against experimental Burkitt's lymphoma in athymic mice. Simultaneous inoculation of EBV- immortalized B cells and Burkitt's lymphoma cells in the same subcutaneous site resulted in tumors that regressed with necrosis and scarring. Similarly, simultaneous inoculation of EBV-immortalized B cells and Burkitt's lymphoma cells in separate subcutaneous sites resulted in regression of a proportion of the Burkitt's tumors. Furthermore, most of the established human Burkitt's tumors regressed with necrosis and scarring after intratumor inoculations with EBV- immortalized B cells. The EBV-immortalized B cells continued to exert this antitumor effect even when killed with irradiation. The experimental approach to Burkitt's lymphoma treatment described here exploits the ability of athymic mice to reject EBV-immortalized B cells to target an effective antitumor response to malignant cells normally incapable of eliciting it. Recently, we have began to study the mechanisms mediating Burkitt's lymphoma regression in this experimental system. Preliminary information suggests that a set of murine cytokines and chemokines produced at the tumor site are responsible for tumor regression.